Rosacea is a chronic inflammatory disease associated with dilation of the facial blood vessels in humans. Rosacea affects the skin of the central face, especially the nose, cheeks, chin and forehead. The disease may progress with age. Rosacea may begin in individuals less than 20 years of age but peaks between the ages of 40 and 50.
Early rosacea is characterized by recurrent episodes of flushing or blushing that often develop into persistent or permanent redness of the skin. Flushing may be triggered by numerous non-specific stimuli including sun exposure, heat, cold, alcoholic drinks, spicy foods, chemical irritation and strong emotions. With time, papules, pustules, blood vessel formation and hypertrophy of sebaceous glands may develop. Symptoms of facial discomfort can include tightness, itching, burning, warmth, stinging and/or tingling.
Classically, treatment includes anti-infectious agents, such as, metronidazole, clindamycin, precipitated sulfur, sodium sulfacetamide, benzoyl peroxide, azelaic acid, or tetracycline-class antibiotics. But these agents do not affect the vascular component of this condition or the resulting skin redness. Other treatment strategies include avoidance of triggering factors, irritating stimuli, and limiting sun exposure.
Lasers are now available to treat some of the telangiectasias and redness in rosacea. An excellent review of the currently available lasers is found in the article: Getting the Red Out, presented in the 6th Annual Acne and Rosacea issue of Skin & Aging, August 2003, pages 74-80. However, as is clearly stated in that review by Michael Krivda, “not all facial vessels respond to currently available laser therapies.”
Furthermore, although some telangiectasias are treatable with laser, treatment of these blood vessels with medications has been completely ineffective. James Q. Del Rosso, DO, clinical assistant professor, Department of Dermatology, University of Nevada School of Medicine, Las Vegas, stated in: Medical Management of Rosacea with Topical Agents: A thorough appraisal of available treatment options and recent advances, Cosmetic Dermatology, August 2003: “Currently available medical therapies for rosacea have not been shown to reduce the number of facial telangiectasias.”
Finally, there is currently no consistently effective treatment of any kind for the acute flushing and blushing of rosacea. John E. Wolf, Jr, MD, professor and chairman of the Department of Dermatology, Baylor College of Medicine, Houston, Tex., addressed this very issue in the meeting highlights for the Fall Clinical Dermatology Conference in Las Vegas, Nev., 2002. According to Dr. Wolf, “By far the most difficult-to-treat and challenging patients with rosacea are the patients who flush and blush. Indeed, no therapy works consistently in these patients.” Dr. Wolf further asserted, “In my opinion, lasers are the most effective treatment for erythemato-telangiectatic rosacea, but I think they are much less effective for flushing and blushing patients. Some patients will respond but most do not.”
Similarly, no consistently effective treatment has existed for the redness that may develop in other forms of discreet skin erythemas particularly those due to vascular cutaneous hyper-reactivity, including the redness associated with acute sunburn, chronic solar damage, inflammatory acne, or emotionally or physiologically induced erythema. These conditions may also be accompanied by itching, burning, or pain with resulting significant irritation for individuals suffering therefrom.
Thus, there exists a need for effective treatment of skin redness and of the state of vascular cutaneous hyper-reactivity as exhibited in rosacea or discreet erythemas.
Although the cause of rosacea is still unknown, it is clear that individuals with this condition exhibit a cutaneous hyper-reactivity with dilation of blood vessels of the skin. An acute dilation of blood vessels leads to periodic episodes of flushing or blushing. The more chronic form, felt to be due to blood vessels dilating over decades and eventually remaining dilated permanently, manifests as permanent redness of the skin or fine visible blood vessel formation (telangiectasias) within the skin.
A plethora of topical dermatological, cosmetic and pharmaceutical preparations and numerous methods and apparati exist for the treatment of rosacea, however, none has been proven consistently effective in treating and/or preventing the vascular dilatation which characterizes the erythema and flushing which are hallmarks of the disease.
A number of patents have been issued related to rosacea treatments. U.S. Pat. No. 4,837,378 to Borgman, describes a topical aqueous gel containing metronidazole and polyacrylic acid for the treatment of rosacea. U.S. Pat. No. 6,174,534 to Richard et al. claims the use of a cosmetic composition containing from 1-5% of a C.sub.12-C.sub.24 fatty acid, from 5 to 15% of an ester of C.sub.12-C.sub.24 fatty acid and of a C.sub.2-C.sub.3 polyalkylene oxide fragment containing from 2 to 100 polyalkylene oxide residues, from 1 to 20% of an optionally polyoxyalkylenated C.sub.12-C.sub.22 fatty acid glyceride containing from 0 to 20 ethylene oxide residues, from 1 to 20% of an ester of a C.sub.12-C.sub.24 fatty acid and of a C.sub.1-C.sub.6 alcohol, from 0.1 to 10% of glycerol, from 0.1 to 3% of a C.sub.12-C.sub.24 fatty alcohol and water, where the composition is free of metronidazole, lanthanide, tin, zinc, manganese, yttrium, cobalt, barium strontium salt, and non-photosynthetic filamentous bacteria.
U.S. Pat. No. 5,972,993 describes a method of treating rosacea with a topically applied compound comprising an antioxidant (“free-radical scavenger”) mixed in an inert vehicle.
U.S. Pat. No. 5,569,651, to Garrison, et al discusses the use of a combination of salicylic acid and lactic acid to treat the sensitive skin of rosacea.
U.S. Pat. No. 5,438,073, to Saurat, et al claims the use of dermatological compositions containing retinoids for the treatment of rosacea.
U.S. Pat. No. 6,180,699 to Tamarkin, et al claims the use of dermatological preparations containing mono or diesters of alpha., .omega dicarboxylic acids for the treatment of the hyperkeratinization and seborrheic components of rosacea.
U.S. Pat. No. 6,176,854 to Cone, claims the use of a Holmium laser system for the coagulation of some of the dilated blood vessels associated with rosacea to attempt to decrease the redness of the condition.
U.S. Pat. No. 6,306,130 describes the use of a methods and apparati for heating and inducing necrosis and degradation of blood vessels with an external energy source (e.g. a laser) to permanently weld blood vessels and treat various conditions such as varicose veins and telangiectasias.
Additionally, new insights and theories regarding the pathogenesis of rosacea have led to the development of treatment strategies focusing on the role of neurotransmitters and other potential mediators of vascular dilatation and hyper-reactivity.
U.S. Pat. No. 5,958,432 to Breton, et al. describes the use of cosmetic/pharmaceutical compositions comprised of an effective Substance P antagonist of at least one beta-adrenergic agonist for the treatment of a variety of mammalian disorders mediated by an increase in the synthesis and/or release of Substance P including cutaneous disorders and sensitive skin and may generally relieve the irritation of rosacea (but has no direct vasoconstrictive properties).
U.S. Pat. No. 5,932,215 to de Lacharriere et al. is directed to the development of therapeutic/cosmetic compositions comprising CGRP (calcitonin gene related peptide) antagonists, Substance P antagonists, for treating skin redness, rosacea and discrete erythema afflicting a mammalian, notably human patient. Individuals are treated by administrating a therapeutically/cosmetically effective amount of at least one CGRP antagonist, advantageously in combinatory mixture with at least one antagonist of a neuropeptide other than CGRP, e.g., a substance P antagonist, and/or at least one inflammation mediator antagonist.
The notion of administering alpha-2 adrenoceptor agonists to alleviate the symptoms of diseases modulated by activity of these receptors has been investigated. U.S. Pat. No. 5,916,900 to Cupps, et al. relates to the use of certain substituted 7-(2-imidazolinylamino)quinolone compounds which have been found to be alpha-2 adrenoreceptor agonists and are useful for the treatment of disorders modulated by alpha-2 adrenoceptors. Such disorders include sinusitis, nasal congestion, numerous pulmonary and cardiovascular disorders, gastrointestinal disorders such as diarrhea, irritable bowel syndrome and peptic ulcer, conditions associated with chronic pain, migraine, and substance-abuse withdrawal syndrome. The subject invention involved novel compounds and compositions which have activity when administered perorally, parenterally, intranasaly and/or topically.
Finally, α1-adrenoceptor agonists have been historically used on ocular mucosal tissue to treat the conjunctival redness associated with allergic and other conditions, and to nasal mucosa as a decongestant for the treatment of allergic rhinitis and other conditions.
Also, U.S. Pat. No. 6,136,337 provides a composition for rectal mucosal administration suitable for curing hemorrhoids which includes an acrylic acid polymer, a vasoconstrictor, including tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylepherine hydrochloride or oxymetazoline hydrochloride and a rectal tissue-curing agent.
Critical to understanding the effects of catecholamines and related sympathomimetic agents is an understanding of the classification and properties of the different types of adrenergic receptors (adrenoceptors) that mediate their response. Although structurally related, different adrenoceptors regulate distinct physiological processes by controlling the synthesis or release of a variety of second messenger chemicals or compounds.
Additional general references of interest are set forth below.    Cross, E. Transdermal penetration of vasoconstrictors-present understanding and assessment of the human epidermal flux and retention of free bases and ion-pairs. Pharm Res. 2003 February; 20(2):270-4.    Daly, C J et al. Cellular Localization and Pharmacological Characterization of Functioning Alpha-1 Adrenoceptors by Fluorescent Ligand Binding and Image Analysis Reveals Identical Binding Properties of Clustered and Diffuse Populations of Receptors. Pharmacology and Experimental Therapeutics. 1998; 286(2):984-990.    Del Rosso, J Q. Medical Management of Rosacea With Topical Agents: A Thorough Appraisal of Available Treatment Options and Recent Advances. Cosmetic Dermatology. 2003; 16(8):47-55.    Hoffman B: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, in Goodman & Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition, edited by Hardman J and Limbird L. New York, N.Y., McGraw-Hill, 2001, pp. 215-249.    Hoffman B and Taylor P: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, in Goodman & Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition, edited by Hardman J and Limbird L. New York, N.Y., McGraw-Hill, 2001, pp. 129-153.    Hudson, A L et al. In vitro and in vivo approaches to the characterization of the alpha2-adrenoceptor. J Auton Pharmacol. 1999 December; 19(6):11-20.    Krivda, M. Getting the Red Out. Skin & Aging. 6th Annual Acne & Rosacea Issue. 2003; 11(8):74-80.    Odom R B et al. Andrews' Diseases of the Skin, Ninth Edition, Philadelphia, W. B. Saunders, 2000, pp 301-303.    Plewig, G et al: Rosacea, in Fitzpatrick's Dermatology in General Medicine, Fifth Edition, edited by Irwin Freedberg et al. New York, N.Y., McGraw-Hill, 1999, pp 785-794.    Wolf J. ‘Toughest Patients’ May Be the Ones You See Each Day. in Meeting Highlights: 21st Anniversary Fall Clinical Dermatology Conference, Las Vegas, Nev., 2002: p. 1-4.